The objective of this project is to analyze host defense mechanisms against viral infection in the model organism Drosophila melanogaster, and to do so in the light of concurrent studies of viral infection in mice, carried out by our colleagues in La Jolla and in Osaka. Like all other organisms, insects are afflicted by viruses and react to viral infections. We posit that by studying the response of Drosophila to viral infection we will uncover evolutionary conserved mechanisms of innate immunity that, together with the programs developed in the other participating laboratories, will help to unravel the essential aspects of the antiviral response in mammals. The project has three specific aims. The first two aims are based on our studies of the global transcriptional response to infection by two RNA viruses. The genes induced by virus infection will be used as markers in forward genetic screens to identify mutations that impair the antiviral response (Specific Aim 1). Moreover, interesting candidate antiviral effector molecules will be selected from the list of genes induced by viral infection, and functionally characterized (Specific Aim 2). The third aim is to provide an extended view of the complete repertoire of responses to virus infection in Drosophila, using microarrays to compare the response to infection in different tissues, to investigate the response to different types of viruses (in particular DMA viruses), and finally, to analyze the response to viral RNA and viral proteins. The relevance of this research to public health will be three-fold. First, characterization of the pristine host defense against viral infection in Drosophila may reveal novel evolutionary conserved pathways of host defense in mammals, as occurred in the case of Toll-like receptors. Second, the Drosophila model may reveal original strategies to counter viral infection that may guide the development of antiviral therapeutics. Third, emerging viral diseases with global impact, such as West Nile virus infection, are transmitted by Aedes mosquitoes, which, like Drosophila, belong to the order Diptera. Our research may shed light on the interaction between arthropod-borne viruses and their insect vectors.